Skip to main content
SpringerLink
Log in

Basic Aspect: Neurorepair After Stroke

  • Chapter
  • First Online:
Stroke Revisited: Pathophysiology of Stroke

Part of the book series: Stroke Revisited ((STROREV))

  • 1375 Accesses

Abstract

This chapter discusses the scientific premise of stem cell-based therapies aimed at repairing damage produced by cerebrovascular insults in the adult human brain. Understanding the principles that govern stem cell biology will be of crucial importance to help designing treatment strategies for regenerative medicine. For this reason, the chapter is divided in two sections. The first part will touch upon pivotal basic research that has paved the way to a fuller comprehension of neurogenesis in the developing and adult brain. Interestingly, many molecular mechanisms that play roles in neurogenesis are shared between brain development and adulthood. Therefore, studies that have focused on brain formation have also guided investigations around homeostatic neurogenesis, as well as regenerative repair of the adult brain. The second section of this chapter will introduce recent biomedical investigations around the possibilities of initiating ectopic neuroregenerative programmes, or boosting physiological cell turnover rates for regenerative repair. In this context, we will discuss opportunities for promoting endogenous neurogenesis that may be generated from actual or potential stem cells residing throughout the brain. Finally, we will discuss experimental approaches aiming to replace lost neurons using endogenous sources.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol. 2000;182(3):311–22.

    Article  CAS  PubMed  Google Scholar 

  2. Gratzner HG. Monoclonal antibody to 5-bromo–and 5-iododeoxyuridine: a new reagent for detection of DNA replication. Science. 1982;218(4571):474–5.

    Article  CAS  PubMed  Google Scholar 

  3. Levin I, Naegler T, Kromer B, Diehl M, Francey RJ, Gomez-Pelaez AJ, Steele LP, Wagenbach D, Weller R, Worthy DE. Observations and modelling of the global distribution and long-term trend of atmospheric 14CO2. Tellus B. 2010;62(1):26–46.

    Article  CAS  Google Scholar 

  4. Spalding KL, Bhardwaj RD, Buchholz BA, Druid H, Frisen J. Retrospective birth dating of cells in humans. Cell. 2005;122(1):133–43.

    Article  CAS  PubMed  Google Scholar 

  5. Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, Bostrom E, Westerlund I, Vial C, Buchholz BA, et al. Dynamics of hippocampal neurogenesis in adult humans. Cell. 2013;153(6):1219–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bergmann O, Liebl J, Bernard S, Alkass K, Yeung MS, Steier P, Kutschera W, Johnson L, Landen M, Druid H, et al. The age of olfactory bulb neurons in humans. Neuron. 2012;74(4):634–9.

    Article  CAS  PubMed  Google Scholar 

  7. Bhardwaj RD, Curtis MA, Spalding KL, Buchholz BA, Fink D, Bjork-Eriksson T, Nordborg C, Gage FH, Druid H, Eriksson PS, et al. Neocortical neurogenesis in humans is restricted to development. Proc Natl Acad Sci U S A. 2006;103(33):12564–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kriegstein A, Alvarez-Buylla A. The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci. 2009;32:149–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Parnavelas JG, Barfield JA, Franke E, Luskin MB. Separate progenitor cells give rise to pyramidal and nonpyramidal neurons in the rat telencephalon. Cereb Cortex. 1991;1(6):463–8.

    Article  CAS  PubMed  Google Scholar 

  10. Altman J. Are new neurons formed in the brains of adult mammals? Science. 1962;135(3509):1127–8.

    Article  CAS  PubMed  Google Scholar 

  11. Kaplan MS, Hinds JW. Neurogenesis in the adult rat: electron microscopic analysis of light radioautographs. Science. 1977;197(4308):1092–4.

    Article  CAS  PubMed  Google Scholar 

  12. Rakic P. Limits of neurogenesis in primates. Science. 1985;227(4690):1054–6.

    Article  CAS  PubMed  Google Scholar 

  13. Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science. 1992;255(5052):1707–10.

    Article  CAS  PubMed  Google Scholar 

  14. Richards LJ, Kilpatrick TJ, Bartlett PF. De novo generation of neuronal cells from the adult mouse brain. Proc Natl Acad Sci U S A. 1992;89(18):8591–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci. 1996;16(6):2027–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH. Neurogenesis in the adult human hippocampus. Nat Med. 1998;4(11):1313–7.

    Article  CAS  PubMed  Google Scholar 

  17. Brown J, Cooper-Kuhn CM, Kempermann G, Van Praag H, Winkler J, Gage FH, Kuhn HG. Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. Eur J Neurosci. 2003;17(10):2042–6.

    Article  PubMed  Google Scholar 

  18. van Praag H, Shubert T, Zhao C, Gage FH. Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci. 2005;25(38):8680–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Ponti G, Obernier K, Alvarez-Buylla A. Lineage progression from stem cells to new neurons in the adult brain ventricular-subventricular zone. Cell Cycle. 2013;12(11):1649–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Schmidt-Hieber C, Jonas P, Bischofberger J. Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature. 2004;429(6988):184–7.

    Article  CAS  PubMed  Google Scholar 

  21. Kheirbek MA, Klemenhagen KC, Sahay A, Hen R. Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders. Nat Neurosci. 2012;15(12):1613–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Goncalves JT, Schafer ST, Gage FH. Adult neurogenesis in the hippocampus: from stem cells to behavior. Cell. 2016;167(4):897–914.

    Article  CAS  PubMed  Google Scholar 

  23. Lepousez G, Valley MT, Lledo PM. The impact of adult neurogenesis on olfactory bulb circuits and computations. Annu Rev Physiol. 2013;75:339–63.

    Article  CAS  PubMed  Google Scholar 

  24. Ernst A, Alkass K, Bernard S, Salehpour M, Perl S, Tisdale J, Possnert G, Druid H, Frisen J. Neurogenesis in the striatum of the adult human brain. Cell. 2014;156(5):1072–83.

    Article  CAS  PubMed  Google Scholar 

  25. Dimou L, Gotz M. Glial cells as progenitors and stem cells: new roles in the healthy and diseased brain. Physiol Rev. 2014;94(3):709–37.

    Article  CAS  PubMed  Google Scholar 

  26. Lledo PM, Merkle FT, Alvarez-Buylla A. Origin and function of olfactory bulb interneuron diversity. Trends Neurosci. 2008;31(8):392–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Llorens-Bobadilla E, Zhao S, Baser A, Saiz-Castro G, Zwadlo K, Martin-Villalba A. Single-cell Transcriptomics reveals a population of dormant neural stem cells that become activated upon brain injury. Cell Stem Cell. 2015;17(3):329–40.

    Article  CAS  PubMed  Google Scholar 

  28. Sawamoto K, Wichterle H, Gonzalez-Perez O, Cholfin JA, Yamada M, Spassky N, Murcia NS, Garcia-Verdugo JM, Marin O, Rubenstein JL, et al. New neurons follow the flow of cerebrospinal fluid in the adult brain. Science. 2006;311(5761):629–32.

    Article  CAS  PubMed  Google Scholar 

  29. Silva-Vargas V, Maldonado-Soto AR, Mizrak D, Codega P, Doetsch F. Age-dependent niche signals from the choroid plexus regulate adult neural stem cells. Cell Stem Cell. 2016;19(5):643–52.

    Article  CAS  PubMed  Google Scholar 

  30. Doetsch F, Garcia-Verdugo JM, Alvarez-Buylla A. Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J Neurosci. 1997;17(13):5046–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ihrie RA, Alvarez-Buylla A. Lake-front property: a unique germinal niche by the lateral ventricles of the adult brain. Neuron. 2011;70(4):674–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tavazoie M, Van der Veken L, Silva-Vargas V, Louissaint M, Colonna L, Zaidi B, Garcia-Verdugo JM, Doetsch F. A specialized vascular niche for adult neural stem cells. Cell Stem Cell. 2008;3(3):279–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Palma V, Lim DA, Dahmane N, Sanchez P, Brionne TC, Herzberg CD, Gitton Y, Carleton A, Alvarez-Buylla A, Ruiz i Altaba A. Sonic hedgehog controls stem cell behavior in the postnatal and adult brain. Development. 2005;132(2):335–44.

    Article  CAS  PubMed  Google Scholar 

  34. Palma V, Ruiz i Altaba A. Hedgehog-GLI signaling regulates the behavior of cells with stem cell properties in the developing neocortex. Development. 2004;131(2):337–45.

    Article  CAS  PubMed  Google Scholar 

  35. Imayoshi I, Kageyama R. The role of notch signaling in adult neurogenesis. Mol Neurobiol. 2011;44(1):7–12.

    Article  CAS  PubMed  Google Scholar 

  36. Lim DA, Tramontin AD, Trevejo JM, Herrera DG, Garcia-Verdugo JM, Alvarez-Buylla A. Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron. 2000;28(3):713–26.

    Article  CAS  PubMed  Google Scholar 

  37. Berg DA, Kirkham M, Wang H, Frisen J, Simon A. Dopamine controls neurogenesis in the adult salamander midbrain in homeostasis and during regeneration of dopamine neurons. Cell Stem Cell. 2011;8(4):426–33.

    Article  CAS  PubMed  Google Scholar 

  38. Kirsche K, Kirsche W. Regenerative processes in the telencephalon of Ambystoma Mexicanum. J Hirnforsch. 1964;7:421–36.

    CAS  PubMed  Google Scholar 

  39. Amamoto R, Huerta VG, Takahashi E, Dai G, Grant AK, Fu Z, Arlotta P. Adult axolotls can regenerate original neuronal diversity in response to brain injury. elife. 2016;5:e13998.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Hol EM, Pekny M. Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system. Curr Opin Cell Biol. 2015;32:121–30.

    Article  CAS  PubMed  Google Scholar 

  41. Goritz C, Dias DO, Tomilin N, Barbacid M, Shupliakov O, Frisen J. A pericyte origin of spinal cord scar tissue. Science. 2011;333(6039):238–42.

    Article  PubMed  CAS  Google Scholar 

  42. Godwin JW, Rosenthal N. Scar-free wound healing and regeneration in amphibians: immunological influences on regenerative success. Differentiation. 2014;87(1-2):66–75.

    Article  CAS  PubMed  Google Scholar 

  43. Tom VJ, Steinmetz MP, Miller JH, Doller CM, Silver J. Studies on the development and behavior of the dystrophic growth cone, the hallmark of regeneration failure, in an in vitro model of the glial scar and after spinal cord injury. J Neurosci. 2004;24(29):6531–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. van Niekerk EA, Tuszynski MH, Lu P, Dulin JN. Molecular and cellular mechanisms of axonal regeneration after spinal cord injury. Mol Cell Proteomics. 2016;15(2):394–408.

    Article  PubMed  CAS  Google Scholar 

  45. Di Maio A, Skuba A, Himes BT, Bhagat SL, Hyun JK, Tessler A, Bishop D, Son YJ. In vivo imaging of dorsal root regeneration: rapid immobilization and presynaptic differentiation at the CNS/PNS border. J Neurosci. 2011;31(12):4569–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Cattin AL, Lloyd AC. The multicellular complexity of peripheral nerve regeneration. Curr Opin Neurobiol. 2016;39:38–46.

    Article  CAS  PubMed  Google Scholar 

  47. Vrbova G, Mehra N, Shanmuganathan H, Tyreman N, Schachner M, Gordon T. Chemical communication between regenerating motor axons and Schwann cells in the growth pathway. Eur J Neurosci. 2009;30(3):366–75.

    Article  PubMed  Google Scholar 

  48. Magnusson JP, Goritz C, Tatarishvili J, Dias DO, Smith EM, Lindvall O, Kokaia Z, Frisen J. A latent neurogenic program in astrocytes regulated by notch signaling in the mouse. Science. 2014;346(6206):237–41.

    Article  CAS  PubMed  Google Scholar 

  49. Yulyaningsih E, Rudenko IA, Valdearcos M, Dahlen E, Vagena E, Chan A, Alvarez-Buylla A, Vaisse C, Koliwad SK, Xu AW. Acute Lesioning and rapid repair of hypothalamic neurons outside the blood-brain barrier. Cell Rep. 2017;19(11):2257–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Gould E. How widespread is adult neurogenesis in mammals? Nat Rev Neurosci. 2007;8(6):481–8.

    Article  CAS  PubMed  Google Scholar 

  51. Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med. 2002;8(9):963–70.

    Article  CAS  PubMed  Google Scholar 

  52. Carlen M, Meletis K, Goritz C, Darsalia V, Evergren E, Tanigaki K, Amendola M, Barnabe-Heider F, Yeung MS, Naldini L, et al. Forebrain ependymal cells are notch-dependent and generate neuroblasts and astrocytes after stroke. Nat Neurosci. 2009;12(3):259–67.

    Article  CAS  PubMed  Google Scholar 

  53. Arsenijevic Y, Villemure JG, Brunet JF, Bloch JJ, Deglon N, Kostic C, Zurn A, Aebischer P. Isolation of multipotent neural precursors residing in the cortex of the adult human brain. Exp Neurol. 2001;170(1):48–62.

    Article  CAS  PubMed  Google Scholar 

  54. Palmer TD, Schwartz PH, Taupin P, Kaspar B, Stein SA, Gage FH. Cell culture. Progenitor cells from human brain after death. Nature. 2001;411(6833):42–3.

    Article  CAS  PubMed  Google Scholar 

  55. Kirschenbaum B, Nedergaard M, Preuss A, Barami K, Fraser RA, Goldman SA. In vitro neuronal production and differentiation by precursor cells derived from the adult human forebrain. Cereb Cortex. 1994;4(6):576–89.

    Article  CAS  PubMed  Google Scholar 

  56. Sanai N, Tramontin AD, Quinones-Hinojosa A, Barbaro NM, Gupta N, Kunwar S, Lawton MT, McDermott MW, Parsa AT, Manuel-Garcia Verdugo J, et al. Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature. 2004;427(6976):740–4.

    Article  CAS  PubMed  Google Scholar 

  57. Faiz M, Sachewsky N, Gascon S, Bang KW, Morshead CM, Nagy A. Adult neural stem cells from the subventricular zone give rise to reactive astrocytes in the cortex after stroke. Cell Stem Cell. 2015;17(5):624–34.

    Article  CAS  PubMed  Google Scholar 

  58. Ohira K, Furuta T, Hioki H, Nakamura KC, Kuramoto E, Tanaka Y, Funatsu N, Shimizu K, Oishi T, Hayashi M, et al. Ischemia-induced neurogenesis of neocortical layer 1 progenitor cells. Nat Neurosci. 2010;13(2):173–9.

    Article  CAS  PubMed  Google Scholar 

  59. Huttner HB, Bergmann O, Salehpour M, Racz A, Tatarishvili J, Lindgren E, Csonka T, Csiba L, Hortobagyi T, Mehes G, et al. The age and genomic integrity of neurons after cortical stroke in humans. Nat Neurosci. 2014;17(6):801–3.

    Article  CAS  PubMed  Google Scholar 

  60. Kokaia Z, Lindvall O. Stem cell repair of striatal ischemia. Prog Brain Res. 2012;201:35–53.

    Article  PubMed  Google Scholar 

  61. Kokaia Z, Thored P, Arvidsson A, Lindvall O. Regulation of stroke-induced neurogenesis in adult brain--recent scientific progress. Cereb Cortex. 2006;16(Suppl 1):i162–7.

    Article  PubMed  Google Scholar 

  62. Benraiss A, Chmielnicki E, Lerner K, Roh D, Goldman SA. Adenoviral brain-derived neurotrophic factor induces both neostriatal and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain. J Neurosci. 2001;21(17):6718–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Benraiss A, Bruel-Jungerman E, Lu G, Economides AN, Davidson B, Goldman SA. Sustained induction of neuronal addition to the adult rat neostriatum by AAV4-delivered noggin and BDNF. Gene Ther. 2012;19(5):483–93.

    Article  CAS  PubMed  Google Scholar 

  64. Liu F, You Y, Li X, Ma T, Nie Y, Wei B, Li T, Lin H, Yang Z. Brain injury does not alter the intrinsic differentiation potential of adult neuroblasts. J Neurosci. 2009;29(16):5075–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hou SW, Wang YQ, Xu M, Shen DH, Wang JJ, Huang F, Yu Z, Sun FY. Functional integration of newly generated neurons into striatum after cerebral ischemia in the adult rat brain. Stroke. 2008;39(10):2837–44.

    Article  CAS  PubMed  Google Scholar 

  66. Cregg JM, DePaul MA, Filous AR, Lang BT, Tran A, Silver J. Functional regeneration beyond the glial scar. Exp Neurol. 2014;253:197–207.

    Article  PubMed  Google Scholar 

  67. Lindvall O, Bjorklund A. Cell therapeutics in Parkinson's disease. Neurotherapeutics. 2011;8(4):539–48.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Lu P, Wang Y, Graham L, McHale K, Gao M, Wu D, Brock J, Blesch A, Rosenzweig ES, Havton LA, et al. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell. 2012;150(6):1264–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Meyer HS, Schwarz D, Wimmer VC, Schmitt AC, Kerr JN, Sakmann B, Helmstaedter M. Inhibitory interneurons in a cortical column form hot zones of inhibition in layers 2 and 5A. Proc Natl Acad Sci U S A. 2011;108(40):16807–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tremblay R, Lee S, Rudy B. GABAergic interneurons in the Neocortex: from cellular properties to circuits. Neuron. 2016;91(2):260–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Martinez-Cerdeno V, Noctor SC, Espinosa A, Ariza J, Parker P, Orasji S, Daadi MM, Bankiewicz K, Alvarez-Buylla A, Kriegstein AR. Embryonic MGE precursor cells grafted into adult rat striatum integrate and ameliorate motor symptoms in 6-OHDA-lesioned rats. Cell Stem Cell. 2010;6(3):238–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden

    Margherita Zamboni, Jens Magnusson & Jonas Frisén

Authors
  1. Margherita Zamboni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jens Magnusson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jonas Frisén
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jonas Frisén .

Editor information

Editors and Affiliations

  1. Department of Neurology, Seoul National University Hospital, Seoul, Korea (Republic of)

    Seung-Hoon Lee

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Science+Business Media Singapore

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Zamboni, M., Magnusson, J., Frisén, J. (2020). Basic Aspect: Neurorepair After Stroke. In: Lee, SH. (eds) Stroke Revisited: Pathophysiology of Stroke. Stroke Revisited. Springer, Singapore. https://doi.org/10.1007/978-981-10-1430-7_18

Download citation

  • DOI: https://doi.org/10.1007/978-981-10-1430-7_18

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-10-1429-1

  • Online ISBN: 978-981-10-1430-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation